This invention relates to a new chemical process, and to new chemical compounds useful as intermediates in said process. More particularly, it relates to a new chemical process for the preparation of penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo. Said new chemical process comprises oxidation of a 6,6-dihalopenicillanic acid or ester thereof readily hydrolyzable in vivo to the corresponding 1,1-dioxide, followed by dehalogenation. Said new chemical compounds useful as intermediates are 6,6-dihalopenicillanic acid 1,1-dioxides and esters thereof readily hydrolyzable in vivo.
Penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo are useful as beta-lactamase inhibitors and as agents which enhance the effectiveness of certain beta-lactam antibiotics when the latter are used to treat bacterial infections in mammals, particularly humans. Previously, penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo have been prepared from 6-bromopenicillanic acid, or ester thereof readily hydrolyzable in vivo, by debromination to give penicillanic acid, or ester thereof readily hydrolyzable in vivo, followed by oxidation to the 1,1-dioxide. See pending U.S. patent application Ser. No. 890,451, filed Mar. 29, 1978; Belgian Pat. No. 867,859, granted Dec. 6, 1978; and West German Offenlegungsschrift No. 2,824,535 for details of methods of preparing penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo.
6-Halopenicillanic acids have been disclosed by Cignarella et al., Journal of Organic Chemistry, 27, 2668 (1962) and in U.S. Pat. No. 3,206,469; hydrogenolysis of 6-halopenicillanic acids to penicillanic acid is disclosed in British Patent Specification No. 1,072,108.
Clayton, Journal of the Chemical Society (London), (C), 2123, (1969), discloses: (a) the preparation of 6,6-dibromo- and 6,6-diiodopenicillanic acid; (b) oxidation of 6,6-dibromopenicillanic acid with sodium periodate, to give a mixture of the corresponding sulfoxides; (c) hydrogenolysis of methyl 6,6-dibromopenicillanate to give methyl 6.alpha.-bromopenicillanate; (d) hydrogenolysis of 6,6-dibromopenicillanic acid, and its methyl ester, to give penicillanic acid and its methyl ester, respectively; and (e) hydrogenolysis of a mixture of methyl 6,6-diidopenicillanate and methyl 6.alpha.-iodopenicillanate to give pure methyl 6.alpha.-iodopenicillanate.
Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976), disclose oxidation of methyl 6,6-dibromopenicillanate with 3-chloroperbenzoic acid to give methyl 6,6-dibromopenicillanate 1,1-dioxide.